The present invention provides novel compounds which are the products of processes having novel intermediates and the use of compounds, including both the novel compounds and the novel intermediates, for the therapeutic or prophylactic treatment of arrhythmic activity. That is, the compounds of the present invention provide antiarrhythmic activity.
Antiarrhythmic activity of compounds which provide therapy is the mainstay of long-term antiarrhythmic treatment. However, clinicians have long sought the "ideal" antiarrhythmic compound. Such a compound has not yet been found.
Antiarrhythmic therapy and compounds providing beneficial antiarrhythmic activity in relation to electrophysiological classes of action, cardiovascular effects, and pharmacokinetic properties are known. See, for example, K. Nademanee, et al., "Advances in Antiarrhythmic Therapy, The Role of Newer Antiarrhythmic Drugs", JAMA, vol. 247, no. 2, pp. 217-222 (Jan. 8, 1982).
Antiarrhythmic activity is dependent on the effect of a compound on the transmembrane potential of caridac tissue. Thus, antiarrhythmic compounds may be classified according to the type of activity that they have on this potential. Transmembrane potential or action potential of a typical spontaneous depolarizing conducting fiber in the heart is reproduced as FIG. 1 in a publication by D. T. Mason, et al. in Cardiovascular Drugs, vol. 1, chapter III, ADIS Press, Sydney (1977). Besides the depolarization phase noted as phase 0 in the Mason, et al. reference figure, other phases 1, 2, 3, and 4, are also shown. It is at the end of phase 3 that the conducting fiber in the heart reaches its maximum level of polarization, at which time the inside of a cell in the fiber is about 90 millivolts more negative than the surrounding fluid. At this point the spontaneously depolarizing cell begins to lose its polarization. This is phase 4 and is known as "automaticity." It is during phase 4 that pacemaker cells, for example, the SA node of the right atrium, establish the heart rate. Loss of polarization is under sympathetic control which via the .beta.-adrenergic receptor increases the heart rate, and is under vagal control which via cholinergic receptors slows the heart rate. Therefore, .beta.-adrenergic blockers, also known as class II antiarrhythmic agents, slow the heart rate by blocking the sympathetic control mechanism.
Phase 0, the depolarization phase, occurs when the transmembrane potential reaches a threshold potential. Such threshold potential is shown by the FIG. 1 noted above to be about -75 mv. The mechanism of depolarization is thought to be by influx of sodium ions and is accompanied by contraction of the cardiac muscle. Regardless of the mechanism, when the threshold potential is reached, a cell capable of undergoing phase 0 depolarization will depolarize. If the threshold is reached due to the untimely depolarization of adjacent diseased tissue the phenomenon of reentrant arrhythmias can result. Phase 0 depolarization determines the conduction velocity of the tissue. By far the greatest number of available antiarrhythmic agents have an effect on this part of the action potential and are known as Class I antiarrhythmic agents. Thus, Class I agents exert their primary effect on phase 0 depolarization. An example of the effect can be seen for quinidine in the FIG. I which is cited above.
Phase 2 of the action potential is associated with a slow inward transmembrane Ca.sup.++ current. The slow channel calcium blockers known as Class IV antiarrhythmic agents have an effect in this phase.
Finally, the repolarization of the tissue is phase 3 and is associated with a rapid efflux of potassium ion.
For a period of time between phase 0 and phase 3 of the action potential the tissue is unresponsive to a second depolarizing stimulus. This period is known as the refractory period; it is directly related to the duration of the action potential. As early as 1970 it was suggested that drugs which prolong the refractory period could prevent or abolish ventricular tachyarrhythmias and fibrillation. The suggestion is reviewed extensively by J. Thomis et al. in "Ann. Reports in Medicinal Chemistry", vol. 18, H. J. Hess, Ed., Academic Press, New York, N.Y., Chapter 11, (1983). Compounds which prolong the refractory period are known as Class III antiarrhythmia agents. Thus, it is now becoming apparent that the Class III rather than the Class I agents are useful for preventing resistant, life-threatening ventricular arrhythmias. See K. Nademanee et al. cited above and B. N. Singh, et al., "A Third Class of Antiarrhythmic Action. Effects on Atrial and Ventricular Intracellular Potentials, and Other Pharmacological Actions on Cardiac Muscle, of MJ 1999 and AH 3474," Br. J. Pharmac., 39, 675-687 (1970).
The compounds, both the novel compounds and the novel intermediates of the present invention are of these Class III type compounds useful for their antiarrhythmic effect.